The clinical objective in treatment of peptic ulcer disease is to decrease gastric acid secretion, based on the principle "no acid, no ulcer." Traditional peptic ulcer disease therapy involves control of diet and the use of antacids and anticholinergics.
There is evidence indicating that histamine may be the final common pathway for stimulation of gastric secretion. This effect of histamine is mediated via H.sub.2 receptors and is not inhibited by the classical antihistamines, which are H.sub.1 receptor blockers. A number of specific H.sub.2 receptor blocking agents (H.sub.2 receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as secretion by other known gastric acid stimulants, and are useful in the treatment of peptic ulcers.
Burimamide (VIa) was the first clinically effective ##STR5## H.sub.2 receptor antagonist. It inhibits gastric secretion in animals and man, but oral absorption is poor. Metiamide (VIb), a subsequently evaluated H.sub.2 antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (VIc) is as effective an H.sub.2 antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug. The half-life of cimetidine is relatively short, thereby necessitating a therapeutic regimen of multi daily doses of 200 mg. tablets. There is thus a need for anti-ulcer agents which are longer acting and/or more potent than cimetidine.
Reviews on the development of H.sub.2 antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976), and in references cited therein.
Our co-pending application Ser. No. 848,959, filed Nov. 7, 1977, now U.S. Pat. No. 4,112,234 (the disclosure of which is incorporated herein by reference) describes and claims novel histamine H.sub.2 receptor antagonists of the formula ##STR6## wherein R.sup.1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, inclusive, and nontoxic, pharmaceutically acceptable salts thereof, which are effective inhibitors of gastric secretion in animals, including man, and which are useful in the treatment of peptic ulcer disease.
Belgian Pat. No. 853,954 (Farmdoc 77515Y) discloses and claims the following process for the preparation of histamine H.sub.2 antagonists, or intermediates therefor: ##STR7## wherein R.sup.1 is hydrogen or (lower)alkyl; R.sup.2 is a group of the formula ##STR8## or is --NR.sup.6 R.sup.7 ; R.sup.6 and R.sup.7 are hydrogen or (lower)alkyl, or taken together with the nitrogen atom, represent piperidine, pyrrolidine or morpholine; R.sup.3 is hydrogen, (lower)alkyl, trifluoromethyl, benzyl, amino or the group --SR.sup.4 ; R.sup.4 is (lower)alkyl, phenyl, benzyl or chlorobenzyl; R.sup.5 is (lower)alkyl or phenyl; and X is hydrogen.
H. Erlenmeyer et al., Helvetica Chimica Acta, 31, 32-40 (1948) describe the compound ##STR9## and its preparation, which is a member of one of the two classes of starting materials utilized in the process aspect of the present invention .